ICOS cooperates with CD28, IL-2, and IFN-[ggr] and modulates activation of human naive CD4 super(+) T cells

• Published in: European Journal of Immunology 2006-01, Vol.36 (10), p.2601-2612
• Main Authors: Mesturini, Riccardo, Nicola, Stefania, Chiocchetti, Annalisa, Bernardone, Ilaria Seren, Castelli, Luca, Bensi, Thea, Ferretti, Massimo, Comi, Cristoforo, Dong, Chen, Rojo, Jose Maria, Yagi, Junji, Dianzani, Umberto
• Format: Article
• Language: English
• ISSN: 0014-2980; 1365-2567
• DOI: 10.1002/eji.200535571

Several sets of data indicate that ICOS regulates cytokine production in activated T cells, but is less effective on naive T cells. This work evaluates ICOS function in human naive CD4 super(+) T cells through an assessment of the effect of soluble forms of the ICOS and CD28 physiological ligands on activation driven by anti-CD3 mAb. ICOS strikingly potentiated secretion of IL-2, IFN- [ggr], IL-10, and TNF-[agr], but not IL-4, promoted by optimal stimulation of CD3+CD28, and it was the key switching-factor of activation when cells received suboptimal stimulation of CD3+CD28 or stimulation of CD3 alone in the presence of exogenous IL-2. In these conditions, blockade of IL-2 and IFN-[ggr] showed that ICOS builds up a positive feedback loop with IFN-[ggr], which required IL-2 and was inhibited by IL-4. By contrast, in the absence of CD28 triggering or exogenous IL-2, ICOS-induced costimulation mainly supported expression of TGF- [bgr]1 and FoxP3 and differentiation of regulatory T cells capable to inhibit proliferation of naive CD4 super(+) T cells driven by allogeneic cells. These data suggest that ICOS favors differentiation of Th effector cells when cooperates with appropriate activation stimuli such as CD3+CD28 or CD3+IL-2, whereas it supports differentiation of regulatory T cells when costimulatory signals are insufficient.